The long-term goal of this proposal is to elucidate the pathogenic mechanisms that are responsible for irreversible neurological disability in Multiple Sclerosis (MS) patients. Our studies are based on the hypothesis that neuronal loss and neuronal pathology are the major determinants of permanent disability in MS. Inflammatory demyelination causes axon transection early in the course of MS, but remains clinically silent because the brain has a remarkable ability to compensate for loss of neuronal function. Continuous neurological decline during secondary progressive MS occurs because the brain can no longer compensate for additional axonal or neuronal loss. Characterizing the full extent of neuronal pathology in MS brains is essential for understanding its pathogenesis and for developing neuroprotection therapies. In this regard, we have identified significant neuronal death and neuronal pathology in demyelinated regions of the cerebral cortex from MS brains. Studies in Specific Aim 1 will correlate cortical demyelination and neuronal pathologies in a prospective analysis of brains from clinically characterized MS patients obtained by rapid autopsy. Neuronal pathology and loss in cortical lesions may contribute substantially to the total disease burden in MS and play a significant role in the progression of secondary progressive (SP- MS). The second Specific Aim will test the hypothesis that progressive neurological disability in SP-MS occurs by a progressive neuronal loss and deafferentiation that is pre- programmed by axonal transection and neuronal degeneration in relapsing-remitting MS but independent of inflammatory lesions during SP-MS. Extreme variation (1-31 yrs) in the rate of neurological decline in relapsing-remitting stage of MS (RR-MS) and a relatively constant decline in SP-MS support this hypothesis. Specific Aim 3 will investigate an animal model of site-specific inflammatory cortical lesions to determine if activated microglia strip synapses from cortical neurons and whether the chemokine MCP-1 is responsible for microglial-neuron associations. Collectively, our studies should identify new targets for therapeutic intervention that will reduce and delay neurodegeneration and the progression of permanent neurological disability in MS patients.